† VERVE-102, a clinical stage in vivo base editing medicine, leads to potent and precise inactivation of PCSK9 in preclinical studies

Abstract

Background/Synopsis

Lipid lowering therapies reduce the risk of major adverse cardiovascular events, but the requirement for lifelong adherence contributes to poor real-world LDL-C control. Gene editing therapies that inactivate the PCSK9 gene in the liver may enable permanent LDL-C lowering after a single infusion. VERVE-102 is a clinical-stage in vivo base editing medicine. The RNA components of VERVE-102 are an mRNA encoding an adenine base editor (ABE) and a guide RNA that targets PCSK9. These components are delivered to hepatocytes by a GalNAc-lipid nanoparticle (LNP) where they are intended to permanently inactivate PCSK9 and lower LDL-C with a single A-to-G base pair change. The addition of a GalNAc targeting ligand to the LNP is expected to provide an additional route for LNP uptake in hepatocytes that is not dependent on the low-density lipoprotein receptor (LDLR), which may be deficient in familial hypercholesterolemia.

Objective/Purpose

Here we describe the translational research supporting ongoing clinical development of VERVE-102.

Methods

Editing potency and risk for off-target editing with VERVE-102 were evaluated in primary human hepatocytes (PHH) in vitro. Mouse and non-human primate (NHP) models were used to characterize in vivo editing, including biodistribution of editing across tissues, risk for germline transmission, editing efficiency and durability in the liver, and the impact of LDLR deficiency on editing potency.

Results

Increasing doses of VERVE-102 led to saturating PCSK9 editing and corresponding near complete elimination of PCSK9 protein secretion in PHH in vitro. There was no evidence for clinically relevant off-target editing in PHH across a panel of ∼6000 candidate sites. Biodistribution studies of editing across tissue types in NHPs showed high specificity for the liver, and there was no evidence for germline transmission of Pcsk9 edits in the offspring of VERVE-102 treated mice. In NHPs, a single infusion of VERVE-102 (3 mg/kg) led to durable mean reductions of 80% and 62% in blood PCSK9 and LDL-C, respectively. Editing efficiency was not dependent on LDLR in Ldlr knockout mouse models.

Conclusions

Gene editing treatments may have the potential to lower blood LDL-C for a lifetime after a single course of treatment. Here we demonstrate that VERVE-102 leads to potent and precise PCSK9 inactivation in PHH and animal models and provide nonclinical proof-of-concept for LDL-C lowering. A first-in-human clinical trial of VERVE-102 (NCT06164730) is ongoing.

Previously Published: Abstract is original but the content will be an encore of a presentation originally given at the European Atherosclerosis Society Congress.